THE DLG 5-113A MUTATION IS ASSOCIATED WITH SUSCEPTIBILITY TO EARLY ONSET INFLAMMATORY BOWEL DISEASE AND DEMONSTRATES A COMPLEX GENOTYPE PHENOTYPE RELATIONSHIP

Abstract

Aims: Genome wide scanning in a cohort of European IBD patients identified a potential IBD locus on chromosome 10. Recently the 113 mutation on the DLG5 gene (Drosophila Discs Large Homolog 5) at 10q23 has been linked to IBD susceptibility in adults. We aimed to study the role of this mutation in a national early-onset population. Methods: Patients diagnosed with IBD <16 years were recruited. Full clinical phenotype including growth data were obtained. Parental DNA was also collected to allow Transmission Disequilibrium Testing (TDT) to be performed (Both parents collected in 69% of cases). The DLG5-113A G·A missense mutation was genotyped using the Taqman system. A validated scoring system for deprivation category (DEPCAT score) was used to judge social class (scored 1-7, 1 = no deprivation 7 = maximum deprivation). Results: A total of 296 patients (197 CD, 73 UC, 26 IC) were analysed. TDT demonstrated an association with IBD (p = 0.045) but not CD(p = 0.18) or UC(p = 0.10). The allele frequency for IBD patients was 12.9%, with no significant differences between CD, UC and IC. 24.9% of patients were carriers of the mutant allele. Carrier status was associated with higher weight and height centile (75-91st) for IBD (p = 0.004, 0.006 respectively) and CD (p = 0.008, p = 0.002 respectively). Carrier status was also associated with higher social class (DEPCAT score 1) for IBD (0.0005) but not CD or UC (p = 0.06 for both). Carrier status was protective for a lower social class (DEPCAT score 3) for IBD and UC (p = 0.02, 0.04 respectively). Mutation carriage was uncommon in CD patients with joint extraintestinal manifestations (EIM's) (5.9% vs. 24.9%), and skin EIM's (erythema nodosum) (9.5% vs. 24.8%) but did not reach statistical significance (p = 0.07, p = 0.11 respectively). Summary: The DLG-5 113A mutation is associated with susceptibilty to IBD in this population. It is associated with higher height and weight centile at diagnosis of IBD and CD, is commoner in the highest social class and is uncommon in the presence of EIM's. Conclusion: The DLG-5 113A mutation confers susceptibility to early onset IBD. In addition, the data reveal complex gene-environmental interactions, and genotype phenotype relationships.